tbuckley/cabot-search huggingface dataset:
Comparing binary efficacy outcomes for systemic immunomodulatory treatments for atopic dermatitis in a living systematic review and network meta-analysis
Authors: Aaron M Drucker, Megan Lam, Rawaan Elsawi, David Prieto-Merino, Rayka Malek, Alexandra G Ellis, Zenas Z N Yiu, Bram Rochwerg, Sonya Di Giorgio, Bernd W M Arents, Tim Burton, Phyllis I Spuls, Jochen Schmitt, Carsten Flohr
Journal: British Journal of Dermatology (2023)

Abstract Background Systemic treatments for atopic dermatitis (AD) are evaluated primarily in placebo-controlled trials with binary efficacy outcomes. In a living systematic review and network meta-analysis (NMA), we previously analysed continuous efficacy measures. Objectives To compare binary efficacy outcomes of systemic treatments for AD. Methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Latin American and Caribbean Health Science Information (LILACS) database, Global Resource for Eczema Trials (GREAT) database and trial registries up to 1 March 2023. We included randomized trials examining ≥ 8 weeks of treatment with systemic immunomodulatory medications for moderate-to-severe AD. We screened titles, abstracts and full texts and abstracted data independently, in duplicate. Outcomes included the proportion of patients achieving at least 50%, 75% and 90% improvements in Eczema Area and Severity Index (EASI 50, EASI 75 and EASI 90, respectively) and Investigator Global Assessment (IGA) success. We performed random-effects Bayesian NMAs to calculate odds ratios (OR) and 95% credible intervals (CrIs) between each intervention for each outcome. Results Eighty-three trials with 22 122 participants were included in the systematic review. In analyses limited to trials of 8–16 weeks’ duration with predominantly adult populations, abrocitinib 200 mg daily (OR 1.5, 95% CrI 1.1–2.2) and upadacitinib 15 mg daily (OR 1.7, 95% CrI 0.9–3.3) and 30 mg daily (OR 2.5, 95% CrI 1.3–5.0) were associated with higher odds of achieving EASI 50 vs. dupilumab. Abrocitinib 100 mg daily (OR 0.7, 95% CrI 0.5–1.0), baricitinib 2 mg daily (OR 0.4, 95% CrI 0.3–0.5) and 4 mg daily (OR 0.5, 95% CrI 0.3–0.7), and tralokinumab (OR 0.4, 95% CrI 0.3–0.6) were associated with lower odds of achieving EASI 50 vs. dupilumab. Results were similar for EASI 75, EASI 90 and IGA success. Conclusions Supporting results for continuous outcome measures, upadacitinib 30 mg daily and abrocitinib 200 mg daily are the most efficacious with regard to binary efficacy endpoints up to 16 weeks in adults with moderate-to-severe AD, followed by upadacitinib 15 mg daily, dupilumab and abrocitinib 100 mg daily. Dupilumab and both doses of upadacitinib and abrocitinib are more efficacious than baricitinib 4 and 2 mg daily and tralokinumab.
Angiotensin II type 1 receptor-associated protein in immune cells: a possible key factor in the pathogenesis of visceral obesity
Authors: Shunichiro Tsukamoto, Toru Suzuki, Hiromichi Wakui, Tatsuki Uehara, Juri Ichikawa, Hiroshi Okuda, Kotaro Haruhara, Kengo Azushima, Eriko Abe, Shohei Tanaka, Shinya Taguchi, Keigo Hirota, Sho Kinguchi, Akio Yamashita, Tomohiko Tamura, Kouichi Tamura
Journal: Metabolism (2023)
Abstract P2161: Stem Cell-derived Exosome Nebulization Therapy (SCENT) Improves Cardiac Function And Tissue Repair In Mice And Pigs
Authors: Junlang Li, DASHUAI ZHU, Ke Huang, Yuan Li, Ke Cheng
Journal: Circulation Research (2023)

Stem cell-derived exosomes show promise as therapeutics for cardiac repair after injury. However, due to their short half-life in vivo, effective treatment typically requires repeated dosing. Previous methods for delivering exosomes to the heart involve invasive injection routes. Here, we report a noninvasive and repeatable approach to exosome delivery via inhalation after myocardial infarction (MI), called Stem Cell-derived Exosome Nebulization Therapy (SCENT). In a mouse model of MI, exosomes were recruited to the ischemic heart after repeated dosing via nebulization. SCENT ameliorated cardiac repair by significantly improving left ventricular function, reducing infarct size, and promoting cardiomyocyte proliferation. Further investigation via single-cell RNA sequencing of the mouse heart after SCENT revealed a significant downregulation of CD36 in endothelial cells (ECs). In an EC- Cd36 fl/- mouse model, we found that inhibiting CD36, a fatty acid transporter in ECs, led to a compensatory increase in glucose utilization in the heart and higher ATP generation, resulting in enhanced cardiac contractility. In a pig model of acute MI, we evaluated functional outcomes using cardiac magnetic resonance imaging (MRI) and found that SCENT led to reduced left ventricular (LV) end-systolic volume (ESV) at day 28 (19.07 ± 3.22 ml) compared to controls (23.60 ± 3.06 ml). Additionally, pigs treated with SCENT exhibited increased LV ejection fraction (EF) (59.36 ±2.84%) and fractional shortening (FS) (29.56 ± 1.25%), further confirming cardioprotection in pigs. Our results pave the way for development of a non-invasive exosome delivery method for rescuing heart injury.
Abstract P1073: The <i>Mir-200</i> Family Modulates Expression Of <i>Tbx5</i> , <i>Gata</i> 4, And <i>Pitx2</i> During Early Cardiac Development.
Authors: Riley J Leonard, Mason Sweat, Steven Eliason, Robert M Weiss, Brad Amendt
Journal: Circulation Research (2023)

Congenital heart defects (CHDs) may be caused by mutations in genes that drive cardiac development. Cardiac development is also regulated at the transcription level. MicroRNAs (miRs) target the transcripts of genes in numerous cardiac cell types during embryonic development. We and others have shown that the miR-200 family modulates the transcripts of cardiogenic transcription factors (TFs) Tbx5 , Gata4 , and Pitx2 ( TGP ). However, relationship between these miRs and cardiogenic TFs during cardiac development is poorly understood. To this relationship, we cultured cardiomyocytes (CMs) with reduced miR-200 expression and found increased expression of Tbx5, Gata4, and Pitx2, providing evidence for targeting in cell-autonomous role. In vivo, the miR-200 family members, miR-200a and -200c , are highly expressed in the developing heart (e14.5) and reduced in adults (2mo) (Ct Value- 200a: 24.3 ± 0.59 v 38.3 ± 0.21; 200c: 25.0 ± 0.64 v 32.5 ± 0.16). Using our miR-200 family inhibitor mice models ( I-200 ), we have found these miRs are required for cardiac development. I-200 embryos are found with a membranous ventral septal defect and poor ventricle wall development, which is lethal by e16.5. At e14.5, I-200 hearts have a significant increase in expression fold change of Tbx5 (5.98 ± 1.51 p ≤ 0.05), Gata4 (3.29 ± 0.61 p ≤ 0.05), and Pitx2 (4.67 ± 0.23 p ≤ 0.05) compared to Wild-Type. With further investigation we discovered the miR-200 family is required for CMs differentiation. I-200 CMs have increased expression of cardiac progenitor markers Nkx2.5 and Mef2c compared to Wild-Type. As these cardiogenic transcription factors target DNA elements required for the maintenance of the CM transcriptome and identity, our data suggests the miR-200 family acts in this process. Concurrent single nuclei multiomics sequencing revealed changes in CM transcription and open chromatin to provided corresponding evidence to support this conclusion. Conclusions: The miR-200 family is a modulator of cardiogenic TFs expression and activity during development. Future directions will determine the role of miR- 200 in adult cardiac disease, such as ischemic injury. Our work provides new insights into gene dosage, modulated by miRs, that is required and necessary during cardiac development.
Abstract P3010: The C10X Polymorphism In The <i>CARD8</i> Gene Is Associated With The Levels Of CCL20 And IL-6 Proteins In Healthy Young Men
Authors: Karin Fransén, Ayako Hiyoshi, Anita Hurtig-Wennlof
Journal: Circulation Research (2023)

Introduction: The Caspase Activation and Recruitment Domain 8 (CARD8) protein is a component of innate immunity which has been associated with regulation of proteins involved in inflammation. We have previously identified CARD8 to act as a regulator of cytokines and chemokines in atherosclerotic lesions, and via knockdown of CARD8 in human umbilical vein endothelial cells (HUVECs). Aim: The present study examines the role of the genetic variation rs2043211 in the CARD8 gene (encoding C10X variant) in relation to a selection of markers of inflammation (Olink inflammation panel; https://olink.com). The CARD8 polymorphism is assumed to mimic the knockdown of CARD8. Methods: DNA was extracted from blood samples from 233 Swedish young healthy men (aged 18.0-25.9 years), collected in the Lifestyle, Biomarkers and Atherosclerosis (LBA) cohort, Örebro University, Sweden. Genotyping of the CARD8 polymorphism was performed with TaqMan real time PCR on DNA from blood samples from young healthy men ( n =233). Protein levels across genotypes were analyzed by additive model (TT vs TA vs AA) by analysis of variance (ANOVA). The recessive (TT + TA vs AA) and dominant (TT vs TA + AA) models were analyzed by t-test. Results: The minor (A) allele of the rs2043211 polymorphism in the CARD8 gene was associated with lower levels of CCL20 and IL-6. The dominant model resulted in p= 0.023 and p= 0.037 for CCL20 and IL-6, respectively. The association remained significant also after adjustment for age and potential intermediate variables (Body Mass Index, low density lipoprotein cholesterol, triglycerides, insulin, and systolic blood pressure). The results agree with previous observations in other cell types. Conclusions: We have shown an association between the polymorphism rs2043211 encoding a truncated variant of the CARD8 gene and lower levels of CCL20 and IL-6 levels in men. Our data indicate that CARD8 may be involved in the regulation of these proteins. Additional in vitro studies are needed to reveal the functional mechanistic effects of the polymorphism. Future longitudinal studies of the polymorphism are warranted to elucidate the clinical effect of these proteins.
Abstract P1060: Correlation Of Plasma Glutathione Peroxidase 4 Concentration With Coronary Heart Disease And The Severity Of Coronary Artery Stenosis
Authors: Dan Song, Rayaan Yunus, Faraz Mahmood, Yifan Bu, Jia Li, Robina Matyal, Hebin Xie, Yiping Leng, Ping Deng, Qiaoqing Zhong
Journal: Circulation Research (2023)

Introduction: Selenium-dependent glutathione peroxidase (GPX4) is an antioxidative, monomeric enzyme that can protect cells from membrane lipid oxidation-linked damage. Given the potential influence of GPX4 concentration on cardiovascular risk, we investigated how GPX4 levels change in patients with coronary heart disease (CHD), and whether GPX4 concentration correlates with the severity of coronary artery stenosis (CAS). Methods: Patients admitted at our institution between August 2022 and January 2023 for suspected CHD and completed coronary angiography were included. Patients were stratified according to their coronary angiography results: CHD group (positive) and control group (negative). The severity of CAS in patients with CHD was evaluated by dividing patients into low (&lt;43 points) or high (≥43 points) Gensini score groups. Plasma GPX4 concentration was measured by enzyme-linked immunosorbent assay (ELISA). Results: Eighty-one patients were included based on our eligibility criteria, 41 patients in the CHD group and 40 patients in the control group. Patients with CHD were more commonly male and hypertensive, and presented with significantly greater levels of triglycerides and LDL-cholesterol at baseline. ELISA analysis indicates that patients with CHD have significantly lower plasma GPX4 concentrations as compared to patients in the control group. Furthermore, Spearman’s correlation analysis shows an inverse association between plasma GPX4 concentration and Gensini score in patients with CHD. Conclusion: Our results suggest that plasma GPX4 concentration was significantly lower in patients with CHD and is negatively correlated with the severity of CAS.
Abstract P2033: Western Diet Can Cause Adverse Cardiac Remodeling During Pregnancy By Inducing Foxo1 Expression
Authors: Yijun Yang, Hajime Kubo, Justin Kurian, Jaslyn Johnson, Yijia Li, Rajika Roy, Remus M Berretta, Walter J Koch, Mohsin Khan, Sadia Mohsin, Steven R Houser
Journal: Circulation Research (2023)

Introduction: Pregnancy induces physiological cardiac hypertrophy in healthy women. Our recent findings suggest that obesity can disturb this process and induce pathological cardiac hypertrophy during pregnancy both in human patients and Western Diet (WD) fed mice. Animal studies determined the pathological cardiac hypertrophy is concomitant with increased cardiomyocyte cross-sectional area (CSA), fetal gene activation and fibrosis, however, the underlying mechanisms remain unclear. The present study asks if FoxO1, as a transcriptional factor, may play a role in the adverse cardiac response to pregnancy in WD mice. Methods: The expression levels of FoxO1 and its downstream targeting genes were tested in Ctrl Diet (CD) and WD fed non-pregnant and postpartum animals. To further investigate the role of FoxO1 in pathological cardiac hypertrophy in WD animals during pregnancy, FoxO1 was then silenced by AAV9-shFoxO1 virus in WD mice before breeding. AAV9-scramble RNA served as control. Cardiac phenotype in AAV9 treated WD mice were characterized at post-partum day 1. Results: WD feeding led to increased gene expression levels of FoxO1 and its downstream targeting genes, such as CD36 and PDK4, compared with CD mice. While the gene expression levels of FoxO1 were not different between non-pregnant and pregnant WD mice, FoxO1 protein activation was significantly increased in WD mice after pregnancy determined by a decrease of pFoxO1/tFoxO1 ratio, compared with non-pregnant WD mice. Silencing FoxO1 inhibited the expression levels of FoxO1 and its downstream genes CD36 and PDK4. FoxO1 inhibition in WD fed animals prevented WD induced pathological hypertrophy during pregnancy, with decreased heart weight, cardiomyocyte CSA, attenuated fetal gene activation and fibrosis accumulation. FoxO1 silencing also led to less accumulation of lipid peroxidation product in the myocardium. Conclusions: FoxO1 activation in WD mice with metabolic disturbances during pregnancy can induce pathological cardiac hypertrophy observed during pregnancy.
Abstract P2041: Identification Of The Nuclear Localization Signal In RBM20 And Its Function In The Pathogenesis Of Dilated Cardiomyopathy
Authors: Yanghai Zhang, Zachery R Gregorich, Yujuan Wang, Camila Braz, Jibin Zhang, Yang Liu, Peiheng Liu, Nanyumuzi Aori, Timothy A Hacker, Henk L Granzier, Wei Guo
Journal: Circulation Research (2023)

Human patients carrying genetic mutations in RNA binding motif 20 (RBM20) develop an aggressive and arrhythmogenic form of dilated cardiomyopathy (DCM). Five of over 900 genetic mutations in RBM20 have recently been validated in animal models. Four of these five mutations are located in the arginine/serine-rich (RS) domain with the fifth in the RNA recognition motif (RRM). Interestingly, only mutations in the RS domain cause severe DCM, which suggests that disruption of RS domain function is crucial for the pathogenesis of DCM. To test this hypothesis, we generated mice expressing RBM20 with an in-frame deletion of the RS domain ( Rbm20 ΔRS ). We show that Rbm20 ΔRS mice manifest DCM with RBM20 mis-localization and granule formation, similar to that in RS domain mutation knock-in (KI) animals. Conversely, mice expressing RBM20 lacking the RRM do not exhibit RBM20 nucleocytoplasmic transport or granule formation, and, similar to RRM mutation KI mice, do not develop DCM. These data suggest that the critical nuclear localization signal (NLS) in RBM20 is located within the RS domain and that disruption of this sequence leads to RBM20 mis-localization and granule formation. In vitro experiments employing sequence deletion plasmids and immunocytochemical staining revealed that the first nine amino acids in the RS domain constitute the core NLS in RBM20, which is further supported by the fact that all three validated DCM-causing mutations are located in this segment. Analysis of plasmids containing DCM-associated mutations in other regions of RBM20, as well as in the non-NLS RS domain sequence, further confirmed that only mutations in the NLS facilitate re-localization and granule formation. Phosphorylation of residues within the NLS has been shown play an important role in protein nucleocytoplasmic transport. To test this, we mutated all phosphorylatable serine residues in the NLS to unphosphorylatable alanine or phosphomimetic aspartate and provide evidence that phosphorylation is dispensable for nucleocytoplasmic transport. Collectively, our findings identify the critical NLS in RBM20 and demonstrate that mutations in this NLS cause severe DCM through disruption of RS domain-mediated nuclear localization and sarcoplasmic granule formation.
Abstract P2040: Pannexin 1 Activation Drives Neutrophil Recruitment In A Murine Model Of Non-ischemic Heart Failure Induced By Isoproterenol
Authors: Caitlin M Pavelec, Nabin Poudel, Emily Orrell, Samantha Thomas, Hannah Luviano, Scott Yeudall, Clint Upchurch, Subramanian Senthivinayagam, Matthew J Wolf, Norbert Leitinger
Journal: Circulation Research (2023)

Pannexin 1 (Panx1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation and blood pressure regulation. Panx1 channel function is inhibited by spironolactone, a frontline therapy for heart failure patients. Despite this, the function of Panx1 in cardiomyocytes and a possible role in heart failure has not yet been studied. To investigate if Panx1 is involved in the development of non-ischemic heart failure, we use an acute (14 day) model of adrenergic stimulation (isoproterenol) to induce non-ischemic heart failure in a novel mouse model we have generated with constitutive deletion of Panx1 in cardiomyocytes by crossing mice expressing loxP-flanked alleles of Panx1 to mice expressing Cre recombinase under the control of the cardiomyocyte specific MyHC6 promoter (Panx1 MyHC6-Cre ). Constitutive deletion of Panx1 in cardiomyocytes had no effect on heart function at baseline, but protected mice against isoproterenol-induced non-ischemic heart failure (15 mg/kg/day isoproterenol, i.p.). Panx1 MyHC6-Cre mice were protected from systolic and diastolic dysfunction and cardiac hypertrophy as measured by echocardiography and heart mass, respectively. Moreover, Panx1 MyHC6-Cre mice demonstrated decreased recruitment of immune cells (CD45 + ), particularly neutrophils (CD11b + , Ly6g + ) to the myocardium as measured by confocal microscopy and flow cytometry. In vitro , treatment of H9c2 rat myoblasts with isoproterenol led to Panx1-dependent release of ATP and Yo-Pro-1 uptake in a dose-dependent manner, as assessed by pharmacological blockade by spironolactone and siRNA-mediated knock-down of Panx1. These data demonstrate that that β-adrenergic stimulation in cardiomyocytes activates Panx1 channels and that Panx1 deficiency in cardiomyocytes protects against non-ischemic heart failure and the associated cardiac dysfunction at least in part by reducing immune cell recruitment. Taken together, our study provides evidence for Panx1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in heart failure patients.
Abstract P2043: Loss Of Full-length Mylk3 Causes Dilated Cardiomyopathy Via A Myl2-independent Mechanism
Authors: Jack L Williams, Christopher J Smith, Giulia Mastroianni, Michelle Stewart, Pedro Cutillas, Andrew Tinker, Lou Metherell
Journal: Circulation Research (2023)

Introduction: We recently discovered C57BL/6N male mice develop dilated cardiomyopathy (DCM) at 12 months, while the closely related C57BL/6J do not. We identified a variant (Chr8:85365179A&gt;T, c.-5T&gt;A) in myosin light chain kinase 3 ( Mylk3 ) in the B/6N substrain that abolishes translation of the predominant transcript (ENSMUST00000034133). MYLK3 phosphorylates many sarcomere proteins, in particular myosin light chain 2 (MYL2), vital for cardiac development and function. We therefore hypothesise this variant drives the DCM in the B/6N mice. Results: To determine whether the Mylk3 variant alone can cause DCM in mice, we generated two novel isogenic mouse lines. The first carries the Mylk3 c.-5T&gt;A variant on the C57BL/6J background. The second carries the ‘wildtype’ Mylk3 variant on the C57BL/6N background (c.-5A&gt;T, C57BL/6N Mylk3.6J ). While wildtype male C57BL/6J mice developed normally, male littermates expressing the mutant Mylk3 allele (C57BL/6J Mylk3.6N ) show signs of DCM at just 4 weeks old, with increased left ventricular diameter and volume, thinning of the posterior wall and a reduced ejection fraction. In contrast, the C57BL/6N mice develop DCM symptoms, but the C57BL/6N Mylk3.6J mice have smaller left ventricles, thicker left ventricular posterior wall and elevated ejection fraction. We assessed MYL2 phosphorylation by western blot, and contradictory to previous reports, found no difference between any of our mice lines. This may be due to the persistence of a shorter Mylk3 isoform that is unaffected by the variant due to a distinct N-terminus (ENSMUST00000122452; D3Z630). There was no difference between the isoforms in their ability to phosphorylate MYL2 suggesting the shorter isoform could compensate. Phosphoproteomics identified over 500 differentially phosphorylated peptides in 3-day old C57BL/6J and C57BL/6J Mylk3.6N mice. These include many key cardiac transcription factors, such as NFATC2 and FOXK1. Conclusion: We hypothesise that loss of MYLK3 may cause dilated cardiomyopathy in our mice by a MYL2-independent mechanism, possibly by altering vital cardiac transcription causing altered heart development.